The effects of thyrotropin-releasing hormone and scopolamine in Alzheimer's disease and normal volunteers

Thyrotropin-releasing hormone (TRH), a neuromodulator and possibly a neurotransmitter in the central nervous system, was shown in a prior study of young normal volunteers to attenuate the memory impairment induced by the anticholinergic drug scopolamine. In the present study, the cognitive, behavioral and physiologic effects of high dose TRH (0.5 mg/kg), both alone and following administration of scopolamine, were examined in 10 Alzheimer's disease (AD) patients (mean age±SD=63.5 years) and 12 older normal volunteers (mean age=64.9±8.8 years). On the day AD subjects received TRH alone, modest but statistically significant improvement from baseline performance was documented on some tests of learning and memory, especially in those with mild dementia severity. In comparing cognitive test performance between the scopolamine alone and scopolamine+TRH conditions, only two test scores were significantly higher in the latter condition. In the group of older volunteers, TRH did not attenuate scopolamine-induced cognitive impairment, contrary to prior findings in a group of younger controls. In fact, older subjects performed worse after receiving scopolamine followed by TRH than after receiving scopolamine alone. In addition, no change from baseline cognitive performance was detected after subjects received TRH alone. These findings raise several questions and speculations on possible age-related changes in the cholinergic system, as well as on the mechanism of the interaction of TRH with the cholinergic system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68371/2/10.1177_026988119200600404.pd

A pilot placebo-controlled study of chronic m-CPP administration in Alzheimer's disease

Meta000000-Chlorophenylpiperazine (m-CPP), a serotonin agonist and metabolite of the anti-depressant trazodone, was administered chronically to eight moderate to severely affected Alzheimer patients to determine whether it would produce improvement in behavioral symptoms complicating this illness. In doses up to 80 mg/day for 16 days, m-CPP was well tolerated and resulted in small but significant increases in anergy and depression-related symptoms compared with placebo. The effects of chronic m-CPP in this study contrast with the reported beneficial effects of the parent compound trazodone and selective 5-HT reuptake inhibitors in treating behavioral symptoms in Alzheimer patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29223/1/0000278.pd

A preliminary study of the effects of nighttime administration of the serotonin agonist, m-CPP, on sleep architecture and behavior in healthy volunteers

The effects of m-chlorophenylpiperazine (m-CPP) (0.5 mg/kg) on sleep architecture and behavior were examined in six healthy volunteers following a single or oral dose of the drug in a randomized, double-blind, placebo-controlled study, m-CPP reduced total leep time (TST) and sleep efficiency in all subjects. Slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep were decreased and stage 1 sleep was prolonged in a majority of subjects. Prominent behavioral and psychological effects were reported in five out of six subjects following m-CPP (but not following placebo) that interfered with sleep. The sleep disruption and behavioral activation following nighttime administration of m-CPP contrasts with the sedative properties of its parent compound, trazodone, suggesting that the hypnotic effect of trazodone is not related to the agonist profile of its metabolite, m-CPP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29486/1/0000572.pd

The TRH stimulation test in Alzheimer's disease and major depression: Relationship to clinical and CSF measures

A blunted thyroid-stimulating hormone (TSH) response to exogenous thyrotropin-releasing hormone (TRH) has been reported to occur consistently in patients with major depression and less consistently in patients with Alzheimer's disease (AD). In this study we compared the TSH response to TRH in a large group (n = 40) of AD patients, elderly patients with major depression (n = 17), and age-matched controls (n = 14) to further characterize how it may relate to clinical variables, baseline thyroid function tests, and cerebrospinal fluid measures. Comparisons of TRH stimulation test response across all three groups revealed that patients with major depression had lower stimulated TSH levels ([Delta]maxTSH) (p 4) levels (p 4 (FT4) level (p < 0.03) and tended to be more severely demented (p < 0.01) than those with a nonblunted response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29132/1/0000171.pd

Acute effects of high-dose thyrotropin releasing hormone infusions in Alzheimer's disease

Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimer's Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46449/1/213_2004_Article_BF00451695.pd

CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression

Decreased cerebrospinal fluid (CSF), somatostatinlike immunoreactivity (SLI) and alterations in the CSF monamine metabolites 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) have been reported in patients with probable Alzheimer's disease (AD) and in patients with major depression. In this study, we found CSF SLI to be significantly lower in a large group of AD patients n = 60) and in a group of age-matched patients with major depression (n = 18) as compared with normal controls (n = 12). Mean CSF, MHPG, 5-HIAA, andHVA levels were not significantly different among diagnostic groups. Within a group of "depressed" AD patients, CSF levels of 5-HIAA showed a significant positive correlation (p = 0.03) with CSF SLI; a similar relationship was found within the group of patients with major depression. Further exploration of the relationship between the somatostatin and serotonin systems may provide clues as to how neuropeptides interact with monoamine neurotransmitters and what role they have in depression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29318/1/0000383.pd

CSF somatostatin in Alzheimer's disease and major depression: Relationship to hypothalamic-pituitary-adrenal axis and clinical measures

Patients with Alzheimer's disease (AD) and major depression have been shown to have overlapping clinical symptoms and biological markers, including decreased concentrations of cerebrospinal fluid (CSF) somatostatin-like immunoreactivity (SLI), which may be related to alterations in the hypothalamic-pituitary-adrenal axis activity. As in prior studies, we found that CSF SLI was significantly decreased in a group of AD patients (N = 49) and a group of elderly patients with major depression (N = 18), as compared with 13 age-matched controls (F[2, 77] = 12.9, p r = 0.49, p r = 0.47, p r = -0.51, p < .03). Clinical measures of dementia severity and depression did not consistently correlate with CSF SLI in either patient group.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31089/1/0000766.pd

TRH attenuates scopolamine-induced memory impairment in humans

The brain tripeptide thyrotropin-releasing hormone (TRH) has been demonstrated to facilitate cholinergic neurotransmission. To test its interaction with the cholinergic system in humans, high-dose TRH (0.5 mg/kg) or placebo was administered intravenously (IV) to normal controls pretreated with scopolamine (0.5–0.75 mg IV), a centrally active muscarinic antagonist, which has been used to model aspects of the memory impairment of normal aging and of dementia. Compared to placebo, TRH markedly attenuated scopolamine-induced impairment of some measures of memory, most notably on a selective reminding task. This cognitive study is the first in humans to suggest a neuromodulatory effect of a peptide on the cholinergic system, and suggests a facilitatory role for TRH in human memory processes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46332/1/213_2005_Article_BF02245795.pd